Project Summary/Abstract Musculoskeletal diseases affect approximately 110 million adults in the United States, and metallic orthopedic implants are widely used to treat these conditions. However, failure of osseointegration and implant- related infections significantly reduce the long-term success of the implants. Current management strategies focus on implant modifications to promote osteogenic property or introduce antimicrobial function. However, none of these modifications can simultaneously address both issues and it is particularly difficult to enhance osseointegration while controlling peri-operative and/or post-operative infections/reinfections caused by bacteria from biofilms formed on the implant surface or pathogen-invaded osteoblasts. This project will use chitosan-based polycationic surface modifications to enhance osteogenic activity of osteoblast, activate the antibiotic susceptibility of bacteria, and prevent invasion of bacteria into osteoblasts. We have demonstrated that treating titanium with sulfuric acid (H2SO4) creates a roughened/porous surface that significantly improve osteogenic activity. Unfortunately, a rough surfaces can also promote bacterial aggregation, leading to implant-related infections and/or device failure. However, after we covalently bonded chitosan onto the H2SO4-treated surface, the resulting chitosan-bonded rough surface showed greatly enhanced osteogenic activity of cells, completely prevented invasion of bacteria into the pre-attached osteoblasts, and significantly activated the antibiotic susceptibility of adherent bacteria. Building on these pilot results, in this proposed project we will further develop the new technology by establishing optimal surface- modification techniques for maximizing the osteogenic/bacteria-resistant performance of the materials. To achieve this, the specific aims of the proposed research are to (1) fabricate new chitosan-based titanium surfaces with a wide range of polycation levels, and evaluate the physical/mechanical properties of the new materials. Polycation levels will be controlled by the content of surface-bonded chitosan, post-acetylation (to reduce cation level) and post-quaternization (to increase cation level) of the bonded chitosan; and (2) evaluate in vitro the bacteria-resistant and osteogenic performance of the new materials. Osteogenic and bacteria- resistant performance will be tested at each polycation level. The 5 samples with the best overall performance will be further evaluated in two bacteria-osteoblast co-culture models. If found to be feasible and efficacious in this R21 study, the new osteogenic and bacteria-resistant technology can significantly improve the quality of orthopedic devices through promoting bony cell growth at the tissue-prosthetic device interfaces and controlling implant-associated infection. This improvement will benefit millions of patients. In addition, the new technology can be used with a broad range of other implantable medical devices to improve the long-term success of the implants, making an even greater positive impact on health.